This invention relates to a process for the production of a thiazolyl alanine derivative which is a nonnatural amino acid by a simple and economical method.
A thiazolyl alanine derivative such as 4-halomethylthiazole, 3-(4-thiazole) alanine, or the like is an important intermediate for the production of ES 6864 described in Synth. Commun., 20, 22, 3570 (1990) as a renin inhibitor and a TRH (thyrotropin-releasing hormone) derivative described in WO 98/08867 which is represented by the the formula (V): 
wherein Y is optionally substituted alkyl. Further, a thiazolyl alanine derivative, a nonnatural amino acid, is useful as a tool of the combinatorial chemistry.
As a process for the production of a thiazolyl alanine derivative, two methods shown below have already been known. The first method consists of the following 3 steps:
(1) a reaction of formaldehyde with phosphorus pentoxide to give thioformamide (Synthesis, 149 (1973)) or
(1xe2x80x2) a reaction of formaldehyde with Lawesson""s reagent to give thioformamide (Bull. Soc. Chim. Belg., 87, 3, 229 (1978)),
(2) a reaction of thioformamide with 1,3-dichloro-2-prooanone to give 4-chloromethylthiazole, and
(3) alkylation, decarboxylation, and optical resolution to give optically active 3-(4-thiazole)alanine (Synth. Commun., 20, 22, 3507(1990) and Chem. Pharm. Bull., 38, 1, 103(1990)).
Step (1) has some problems such as difficulty of waste disposal, because insoluble products in the reaction mixture have bad smell peculiar to sulfur compounds and do not dissolve in water and any organic solvent except for dimethylsulfoxide. The step (1xe2x80x2) is not appropriate for large scale synthesis because Lawesson""s reagent is expensive. Further, as regards the step (2), 1,3-dichloro-2-propanone has a tearing property.
The second method for the production of a thiazolyl alanine derivative consists of the following 2 steps:
(1) a reaction of diethyl (3-bromo-2-oxo-propyl)acetamide malonate with thioformamide to give diethyl (4-thiazolylmethyl)acetamide malonate and
(2) hydrolysis, decarboxylation, and optical resolution using esterase to give optically active 3-(4-thiazole)alanine (U.S. Pat. No. 5,275,950).
In this method, use of thioformamide is also necessary as described in the above method.
The object of the present invention is to provide a process for the simple and economical production of a thiazolyl alanine derivative which is a nonnatural amino acid. The thiazolyl alanine derivative is useful as an intermediate of medicaments and a tool of the combinatorial chemistry.
The present inventors have found a process, using 4-methylthiazole as a starting material, for the production of a thiazolyl alanine derivative, which is suitable for large scale synthesis.
This invention relates to A) a process for the production of a compound represented by the formula (I): 
wherein R1 is hydrogen or halogen and Hal is halogen, which comprises reacting 4-methylthiazole with N-halosuccinimide in a solvent in the presence of a radical initiator.
In more detail, the invention relates to B) a process for the production of a compound represented by the formula (II): 
wherein R2xe2x80x2 is hydrogen or an amino protective group, or the formula (IV): 
wherein R2xe2x80x3 is different from R2xe2x80x2 and hydrogen or an amino protective group, which comprises,
(a) preparing a compound represented by the formula (I): 
xe2x80x83wherein R1 is hydrogen or halogen and Hal is halogen, by reacting 4-methylthiazole with N-halosuccinimide in a solvent in the presence of a radical initiator,
(b) preparing a compound represented by the formula (I): 
xe2x80x83wherein R1 is as defined above, R2 is an amino protective group, and R3 is lower alkyl, by reacting a compound represented by the formula (I) with R2NHCH(COOR3)2, wherein R2 and R3 are as defined above, in the presence of a base,
(c) dehalogenating the compound represented by the formula (II) when R1 is halogen, and,
(d) preparing a compound represented by the formula (III) by subjecting the compound represented by the formula (II) to hydrolysis, decarboxylation, and optical resolution.
C) A process for the production of a compound represented by the formula (V): 
wherein Y is optionally substituted alkyl, which comprises subjecting a compound represented by the formula (III) or (IV) to a peptide bond formation reaction.
D) A process as described in any one of A) to C) wherein the solvent is chlorobenzene, the radical initiator is 2,2-azobisisobutyronitrile, and N-halosuccinimide is N-chlorosuccinimide.
E) A process as described in any one of A) to C) wherein the solvent is carbon tetrachloride, the radical initiator is 2,2-azobisisobutyronitrile, and N-halosuccinimide is N-bromosuccinimide.
F) A process as described in any one of A) to C) wherein the solvent is carbon tetrachloride, the radical initiator is benzoyl peroxide, and N-halosuccinimide is N-bromosuccinimide.
G) A process for the production of 4-chloromethylthiazole comprising,
(e) reacting 4-methylthiazole with N-chlorosuccinimide in chlorobenzene in the presence of 2,2-azobisisobutyronitrile and
(f) treating the compound obtained in the step (e) with hydrochloric acid to give the corresponding hydrochloride, followed by decarboxylation.
H) A process for the production of a compound represented by the formula (III): 
wherein R2xe2x80x2 is as defined above, or the formula (IV): 
wherein R2xe2x80x3 is as defined above, which comprises,
(g) preparing 5-bromo-4-bromomethylthiazole by reacting 4-methylthiazole with N-bromosuccinimide in carbon tetrachloride in the presence of benzoyl peroxide,
(h) preparing a compound represented by the formula (VI): 
xe2x80x83wherein R2 and R3 are as defined above, by reacting 5-bromo-4-bromomethylthiazole with R2NHCH(COOR3)2, wherein R2 and R3 are as defined above in the presence of a base, and
(i) subjecting the compound represented by the formula (VI) to dehalogenation, hydrolysis, decarboxylation, and optical resolution.
The above steps (d) and (i) are preferred to be carried out successively in order of hydrolysis, decarboxylation, and optical resolution.
The peptide bond formation reaction in the step C) is preferred to be carried out twice in appropriate order.
The term xe2x80x9chalogenxe2x80x9d herein used includes fluoro, chloro, bromo, and iodo. Preferred are chloro and bromo.
The term xe2x80x9clower alkylxe2x80x9d herein used includes straight or branched C1-C6 chain alkyl. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, and the like. Preferably, methyl and ethyl are exemplified.
Examples of xe2x80x9can amino protective groupxe2x80x9d are acetyl and n-butyryl.
The term xe2x80x9coptionally substituted alkylxe2x80x9d herein used includes C1-C6 straight or branched chain alkyl or C3-C8 cycloalkyl which is optionally substituted at any possible position(s) with one or more substituents, for example, hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, carbamoyl, alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SOPRA (p is an integer of 1 to 3, and RA is hydrogen or alkyl), PO(OH)2 or P(O)OH each is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), optionally substituted aryl (e.g., phenyl and tolyl), optionally substituted heteroaryl, an optionally substituted non-aromatic heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, non-aromatic heterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino, alkyloxyamino, formyl, and the lile. Examples of optionally substituted alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl, piperidinomethyl, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, morpholinocarbonylmethyl, acetyloxymethyl, and the like. As a preferable substituent, phenyl, hydroxy, alkylcarbonyloxy, morpholino, piperidino, N-alkyl substituted piperazinyl, alkylcarbonyl, morpholinocarbonyl, and acyloxy are exemplified.
Examples of xe2x80x9csolventxe2x80x9d are carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,4-dioxane, cyclohexane, sulfolane, chlorobenzene, bromobenzene, trifluoromethylbenzene. Preferably, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene are exemplified.
Examples of xe2x80x9cradical initiatorxe2x80x9d are 2,2-azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO).
The present process is described as the following schemes and explained in more detail.

wherein R2 and R3 are as defined above.
Step 1-1
Compound (VII), a commercially available chemical reagent is dissolved in a solvent such as carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,4-dioxane, cyclohexene, sulfolane, chlorobenzene, bromobenzene, trifluoromethylbenzene, preferably, carbon tetrachloride, chlorobenzene, and the like. To this solution are added 0.9 to 1.5 eq., preferably 1.0 to 1.2 eq. of N-chlorosuccinimide and 0.05 to 0.2 eq., preferably 0.05 to 0.1 eq. of AIBN or BPO at 60 to 160xc2x0 C., preferably at reflux and the resulting mixture is stirred for 5 to 30 min., preferably 10 to 20 min. Usual after-treatment gives 4-chrolomethylthiazole.
Step 1-2
The compound obtained in the above step is treated with hydrochloric acid to give compound (VIII). For example, this reaction is carried out as follows: the starting material is dissolved in a solvent such as ethyl acetate, toluene, or the like, then 1 to 4 N hydrochloric acid in ethyl acetate etc. is added to the mixture, and the precipitated crystalline is collected.
Step 2 (Desalting reaction)
To a solution of compound (VIII) in water, and was added an organic solvent such as toluene, ethyl acetate or the like, then sodium hydrogencarbonate, sodium carbonate, etc. is added to the mixture to give the compound (IX).
Step 3
To a solution of sodium methoxide (1.0 to 1.2 eq., preferably 1.0 to 1.1 eq.) in methanol or a solution of sodium ethoxide (1.0 to 1.2 eq., preferably 1.0 to 1.1 eq.) in ethanol is added R2 NHCH(COOR3)2 (0.8 to 1.2 eq., preferably 0.9 to 1.0 eq.), wherein R2 and R3 are as defined above, and the mixture is stirred for 1 to 5 h, preferably 1.5 to 3 h at 50 to 100xc2x0 C., preferably at reflux. Then, to the mixture is added a solution of compound (IX) in methanol or ethanol at 25 to 70xc2x0 C., preferably 50 to 60xc2x0 C. and the resulting mixture is stirred for 1 to 6 h, preferably 2 to 4 h at the same temperature. Usual after-treatment gives compound (X).
Step 4 (Hydrolysis and decarboxylation)
This step is carried out under usual conditions for hydrolysis and decarboxylation. For example, compound (X) is suspended in 1 to 4 N sodium hydroxide aq. and the mixture is stirred for 0.5 to 3 h, preferably 1 to 2 h at 25 to 100xc2x0 C., preferably 25 to 50xc2x0 C. (hydrolysis). To this solution is added conc. hydrochloric acid for adjusting the pH to 3 to 4, preferably 3.5 and the mixture is stirred for 1 to 5 h, preferably 2 to 4 h at 70 to 100xc2x0 C., preferably 100xc2x0 C. while keeping the pH about 4. Usual after-treatment gives compound (XI).
Step 5 (Optical Resolution)
This step is the hydrolysis of the N-acyl group of the L-isomer or D-isomer, using an enzyme such as acylase. The selection of the enzyme leads to obtain an amino acid which has a desired configuration (Agric. Biol. Chem., 44, 1089-1095 (1980) and xe2x80x9cKikankagakusousetsuxe2x80x9d, No. 6 (1989), 97-99, Chemical Society of Japan). The purification is carried out more easily by protecting the amino group of the resulting amino acid with a protective group such as Boc.

wherein R2 and R3 are as defined above.
Step 1
Compound (VII), a commercially available chemical reagent is dissolved in a solvent such as carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,4-dioxane, cyclohexene, sulfolane, chlorobenzene, bromobenzene, trifluoromethylbenzene, preferably, carbon tetrachloride, chlorobenzene, or the like. To this solution are added 0.5 to 1.5 eq., preferably 0.8 to 0.9 eq. of N-bromosuccinimide and 0.02 to 0.2 eq., preferably 0.05 to 0.1 eq. of AIBN at 60 to 160xc2x0 C., preferably at reflux and the resulting mixture is stirred for 5 to 30 min., preferably 10 to 20 min. Usual after-treatment gives compound (XIV).
Step 2
To a solution of sodium methoxide (0.7 to 1.2 eq., preferably 0.8 to 1.1 eq.) in methanol or a solution of sodium ethoxide (0.7 to 1.2 eq., preferably 0.8 to 1.1 eq.) in ethanol is added R2 NHCH(COOR3)2 (0.7 to 1.2 eq., preferably 0.8 to 1.0 eq.), wherein R2 and R3 are as defined above, and the resulting mixture is stirred for 1 to 5 h, preferably 1.5 to 3 h at 50 to 80xc2x0 C., preferably at reflux. Then, to the mixture is added a solution of compound (XIV) in methanol or ethanol at 25 to 70xc2x0 C., preferably 50 to 60xc2x0 C. and the resulting mixture is stirred for 1 to 6 h, preferably 2 to 4 h at the same temperature. Usual after-treatment gives compound (X).
Step 3
This step may be carried out according to Production Example 1xe2x80x94Step 4 to 5.

wherein R2 and R3 are as defined above.
Step 1
Compound (VII), a commercially available chemical reagent is dissolved in a solvent such as carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,4-dioxane, cyclohexene, sulfolane, chlorobenzene, bromobenzene, trifluoromethylbenzene, preferably, carbon tetrachloride, chlorobenzene, or the like. To this solution are added 1.8 to 3.0 eq., preferably 2.0 to 2.5 eq. of N-bromosuccinimide and 0.02 to 0.5 eq., preferably 0.2 to 0.3 eq. of BPO at 60 to 160xc2x0 C., preferably at reflux and the resulting mixture is stirred for 5 to 30 min., preferably 10 to 20 min. Usual after-treatment gives compound (XV).
Step 2
To a solution of sodium methoxide (0.8 to 1.5 eq., preferably 1.0 to 1.2 eq.) in methanol or a solution of sodium ethoxide (0.8 to 1.5 eq., preferably 1.0 to 1.2 eq.) in ethanol is added R2 NHCH(COOR3)2 (0.8 to 1.5 eq., preferably 0.8 to 1.0 eq.), wherein R2 and R3 are as defined above and the resulting mixture is stirred for 1 to 5 h, preferably 1.5 to 3 h at 50 to 80xc2x0 C., preferably at reflux. Then, to the mixture is added a solution of compound (XV) in methanol or ethanol at 25 to 80xc2x0 C., preferably 50 to 60xc2x0 C., and the resulting mixture is stirred for 1 to 6 h, preferably 2 to 4 h at the same temperature. Usual after-treatment gives compound (XVI).
Step 3 (Dehalogenation)
This step is able to be carried out by usual dehalogenation. For example, to a solution of compound (XVI) in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, or the like, preferably methanol, is added a catalyst such as Pdxe2x80x94C, PtO2, Rhxe2x80x94Al2O3, Raney nickel, or the like, preferably Pdxe2x80x94C and the resulting mixture is hydrogenated for 1 to 5 h, preferably 2 to 3 h, at 0 to 100xc2x0 C., preferably 20 to 30xc2x0 C. under 1 to 3 atm., preferably 2 to 3 atm.
Step 4
This step is able to be carried out in a manner similar to that described in Production Example 1xe2x80x94Step 4 to 5.
The compound (V) is synthesized through two peptide bond formation reactions. For example, the synthesis method of the compound (Vxe2x80x2) using the compound (VIII) which is synthesized by the above method is shown below. 
wherein R4 is a carboxy protective group and Y is as defined above.
Step 1 (Protection of carboxy)
The carboxy group of compound (XIII) obtained in Production Examples 1 to 3 is protected as ester such as methyl ester, benzyl ester, t-butyl ester, diphenylmethyl ester, or the like protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons)). For example, when the carboxy group is protected as diphenylmethyl ester, compound (XIII) is dissolved in a mixed solvent of alcohol solvent such as methanol, ethanol, or the like and a solvent such as tetrahydrofuran, dioxane, or the like. To the mixture is added dropwise 1 to 3 eq., preferably 1 to 2 eq. of diphenyldiazomethane over 10 min to 1 h, preferably 20 to 40 min at 0 to 50xc2x0 C., preferably 20 to 40xc2x0 C. and the resulting mixture is stirred for 30 min to 3 h, preferably 1 to 2 h at the same temperature. Usual after-treatment gives compound (XVII).
Step 2 (Peptide bond formation reaction)
This reaction is carried out in accordance with a usual peptide bond formation reaction described in xe2x80x9cPeptide Synthesisxe2x80x9d, Nobuo Izumiya, Maruzen or the like.
As a usual peptide bond formation reaction, exemplified are the method using a condensing agent such as N,N-dicyclohexylcarbodiimide (DCC) or the like, the azide method, the acid chloride method, the acid anhydride method, the activated ester method, or the like. When the starting material has a substituent (e.g., amino, carboxy, and hydroxy) interfering with this peptide bond formation reaction, the substituent may be protected in advance according to the method of xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d Theodora W. Green (John Wiley and Sons), and then deprotected at an appropriate step. For example, compound (XVII) and (R)-(+)-2-methylpyrrolidine hydrochloride which is synthesized by the method described in Tetrahedron, 27, 2599 (1971) are dissolved in a solvent such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, or the like and to this solution are added a base such as triethylamine or the like and a solution of dicyclohexylcarbodiimide (DCC) in N,N-dimethylformamide at xe2x88x9210 to 10xc2x0 C., preferably under ice-cooling. 1-Hydroxybenzotriazole may be added to the reaction mixture, if necessary. The resulting mixture is stirred for 1 h to 1 day, preferably 5 to 10 h at 10 to 50xc2x0 C., preferably 20 to 30xc2x0 C. Usual after-treatment gives to give compound (XVIII).
Step 3 (Deprotection of R4 and Peptide Bond Formation Reaction)
This step may be carried out by a usual deprotection reaction in accordance with the method described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons). For example, when R5 is diphenylmethyl, anisole and trifluoroacetic acid are added to compound (XVIII) at xe2x88x9210 to 10xc2x0 C., preferably under ice-cooling and the mixture is stirred for 5 to 30 min, preferably 10 to 20 min at the same temperature. The resulting mixture is warmed to 20 to 40xc2x0 C. and stirred for 1 to 4 h, preferably 2 to 3 h. Usual after-treatment gives the deprotected compound.
This deprotected compound is reacted with a pyrrolidine derivative in a peptide bond formation reaction according to the above Step 2 to give compound (Vxe2x80x2).

wherein R5 is an amino protective group and Y is as defined above.
Step 1 (Protection of an Amino Group)
The amino group of compound (XIII) synthesized in Production Examples 1 to 3 is protected by an amino protective group such as t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthloyl, trifluoroacetyl, or the like (Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons)). For example, when the amino group is protected by t-butyloxycarbonyl, compound (XIII) is dissolved in a solvent such as dioxane, tetrahydrofuran, acetonitrile, or the like, and Boc2O is added to the mixture at 0 to 50xc2x0 C., preferably 10 to 30xc2x0 C., then the resulting mixture is stirred for 1 to 5 h, preferably 2 to 4 h. Usual after-treatment gives compound (XIX).
Step 2 (Peptide Bond Formation Reaction)
This step can be carried out in a manner similar to that described in Production Example 4 xe2x80x94Step 2.
Step 3 (Deprotection of R5 and Peptide Bond Formation Reaction)
For example, when the amino protective group is t-butyloxycarbonyl, compound (XIX) is dissolved in a solvent such as ethyl acetate or the like, and 1 to 4N hydrochloric acid in ethyl acetate is added to the mixture at xe2x88x9210 to 30xc2x0 C., preferably under ice-cooling, then the mixture is stirred for 1 to 5 h, preferably 2 to 3 h at the same temperature. Usual after-treatment gives the deprotected compound.
This deprotected compound is reacted in a manner similar to that described in the above peptide bond formation reaction to give compound (Vxe2x80x2).
Abbreviations described below are used in the following examples.
Ac: acetyl
Boc: tert-butyloxycarbonyl